Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes.
Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes.
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DOI：
10.1155/2016/1340156
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发表时间：
2016
影响因子：
4.6
通讯作者：
Ward PA
中科院分区：
文献类型：
--
作者：
Haggadone MD;Grailer JJ;Fattahi F;Zetoune FS;Ward PA
C5 a是由补体激活产生的炎性介质，其积极调节免疫防御的各个分支，包括Toll样受体4（TLR 4）信号传导。NOD样受体含pyrin结构域蛋白3（NLRP 3）炎性体被病原体产物和细胞/组织损伤产物激活，并且是IL-1β的主要贡献者。在这项研究中，我们调查是否C5 a调节脂多糖-（LPS-）诱导的NLRP 3炎性小体激活骨髓细胞。与野生型小鼠相比，C5 aR 1 −/−小鼠内毒素血症期间血浆IL-1β的出现减少。在体外，C5 a显著增强了LPS诱导的骨髓Ly 6C高炎症单核细胞中IL-1β的产生，伴随着细胞内IL-1β原表达的增加。在SB 203580阻断p38和不存在C5 aR 1的情况下，这种作用被消除。相反，C5 a抑制LPS诱导的巨噬细胞产生IL-1β，这伴随着pro-IL-1β、NLRP 3和caspase-1表达水平的减弱。C5 a的抑制作用被否定在磷酸肌醇3-激酶（PI 3 K）抑制渥曼青霉素，但在很大程度上保留在C5 aR 1的情况下。因此，C5 a在单核细胞中双向放大TLR 4介导的NLRP 3炎性体活化，同时在巨噬细胞中抑制该途径。然而，由于C5 aR 1缺陷减弱了体内IL-1β对LPS攻击的反应，我们的结果表明C5 a总体上增强了生理性炎性小体反应。
C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1β. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1β during endotoxemia was reduced in C5aR1−/− mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1β in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1β expression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1β, which was accompanied by attenuated levels of pro-IL-1β, NLRP3, and caspase-1 expression. C5a's suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1β response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses.